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PubMed2005

Annotated proteome of a human T-cell lymphoma.

As the reliable identification of proteins by tandem mass spectrometry becomes increasingly common, the full characterization of large data sets of proteins remains a difficult challenge. Our goal was to survey the proteome of a human T-cell lymphoma-derived cell line in a single set of experiments and present an automated method for the annotation of lists of proteins. A downstream application of these data includes the identification of novel pathogenetic and candidate diagnostic markers of T-cell lymphoma. Total protein isolated from cytoplasmic, membrane, and nuclear fractions of the SUDHL-1 T-cell lymphoma cell line was resolved by SDS-PAGE, and the entire gel lanes digested and analyzed by tandem mass spectrometry. Acquired data files were searched against the UniProt protein database using the SEQUEST algorithm. Search results for each subcellular fraction were analyzed using INTERACT and ProteinProphet. All protein identifications with an error rate of less than 10% were directly exported into excel and analyzed using GOMiner (NIH/NCI). The Gene ontology molecular function and cell location data were summarized for the identified proteins and results exported as user-interactive directed acyclic graphs. A total of 1105 unique proteins were identified and fully annotated, including numerous proteins that had not been previously characterized in lymphoma, in functional categories such as cell adhesion, migration, signaling, and stress response. This study demonstrates the utility of currently available bioinformatics tools for the robust identification and annotation of large numbers of proteins in a batchwise fashion.

Algorithms↗
PubMedDate not supplied

JenPep: a novel computational information resource for immunobiology and vaccinology.

JenPep is a relational database containing a compendium of thermodynamic binding data for the interaction of peptides with a range of important immunological molecules: the major histocompatibility complex, TAP transporter, and T cell receptor. The database also includes annotated lists of B cell and T cell epitopes. Version 2.0 of the database is implemented in a bespoke postgreSQL database system and is fully searchable online via a perl/HTML interface (URL: http://www.jenner.ac.uk/JenPep).

ATP-Binding Cassette Transporters↗
PubMed2006

2-DE proteome analysis of a proliferating and differentiating human neuronal stem cell line (ReNcell VM).

The proteome of a proliferating human stem cell line was analyzed and then utilized to detect stem cell differentiation-associated changes in the protein profile. The analysis was conducted with a stable human fetal midbrain stem cell line (ReNcell VM) that displays the properties of a neural stem cell. Therefore, acquisition of proteomic data should be representative of cultured human neural stem cells (hNSCs) in general. Here we present a 2-DE protein-map of this cell line with annotations of 402 spots representing 318 unique proteins identified by MS. The subsequent proteome profiling of differentiating cells of this stem cell line at days 0, 4 and 7 of differentiation revealed changes in the expression of 49 identified spots that could be annotated to 45 distinct proteins. This differentiation-associated expression pattern was validated by Western blot analysis for transgelin-2, proliferating cell nuclear antigen, as well as peroxiredoxin 1 and 4. The group of regulated proteins also included NudC, ubiquilin-1, STRAP, stress-70 protein, creatine kinase B, glial fibrillary acidic protein and vimentin. Our results reflect the large rearrangement of the proteome during the differentiation process of the stem cells to terminally differentiated neurons and offer the possibility for further characterization of specific targets driving the stem cell differentiation.

Blotting, Western↗
PubMed2026

Coordinated inflammatory macrophage and vascular smooth muscle cell remodeling signatures in human atherosclerosis: An integrative single-cell and bulk transcriptomic analysis.

Atherosclerotic plaque progression is shaped by coordinated inflammatory and remodeling programs involving immune cells and vascular wall cells. Inflammatory macrophage activation and vascular smooth muscle cell (VSMC) phenotypic remodeling are central features of human atherosclerosis, but their transcriptomic relationships during plaque progression remain incompletely characterized. This study integrated single-cell and bulk transcriptomic datasets to examine highly inflammatory macrophage states, VSMC remodeling-related transcriptional programs, and candidate ligand-receptor expression patterns in human atherosclerotic plaques. Human atherosclerotic plaque single-cell RNA sequencing data from GSE260657 and bulk transcriptomic data from GSE28829 were analyzed. After quality control, 7628 cells were retained for single-cell analysis. Major cell types were annotated using canonical markers, followed by reclustering of macrophages and VSMC-related cells. Functional module scoring, differential expression analysis, Gene Ontology biological process enrichment, and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed to characterize macrophage transcriptional states. Slingshot was applied to infer VSMC pseudotime ordering. CellChat and NicheNet were used to prioritize candidate ligand-receptor expression patterns and ligand-associated VSMC target gene programs. External bulk transcriptomic analysis was performed to examine whether single-cell-derived inflammatory and remodeling signatures were represented at the tissue-transcriptome level during plaque progression. Macrophage reclustering identified a highly inflammatory macrophage state characterized by prominent inflammatory activation, cytokine-response, and stress-response features. Genes upregulated in this population were enriched in pathways related to tumor necrosis factor (TNF) response, nuclear factor kappa B signaling, leukocyte activation, cytokine signaling, lipid and atherosclerosis, toll-like receptor signaling, and inflammasome-associated inflammation. VSMC reclustering revealed contractile VSMCs, PTHLH+ synthetic VSMCs, KRT7+ VSMC-like cells, interferon-responsive VSMCs, pericyte-like mural cells, and osteogenic/modulated VSMCs. Pseudotime analysis showed a broad contractile-to-osteogenic/modulated transcriptional continuum accompanied by increased expression of remodeling-associated genes and selected inflammatory or remodeling-associated receptor genes. CellChat and NicheNet analyses prioritized candidate ligand-receptor and ligand-associated target gene expression patterns involving SPP1-CD44, TNF-TNFRSF1A, IL1B-IL1R1/IL1RAP, MIF-ACKR3, PDGFB-PDGFRB, and FN1-SDC1/ITGB1. In GSE28829, inflammatory macrophage-, osteogenic/modulated VSMC-, candidate ligand-receptor expression-, SPP1-CD44 candidate axis-, and NicheNet-prioritized target program-related signatures were more prominent in advanced plaques and were positively correlated with each other. This integrative transcriptomic analysis identified a highly inflammatory macrophage state and a VSMC remodeling continuum in human atherosclerotic plaques. Candidate ligand-receptor and ligand-associated target gene expression patterns linked inflammatory macrophage activation with osteogenic/modulated VSMC remodeling at the computational level. External bulk data further showed coordinated enrichment of inflammatory and remodeling signatures in advanced plaques. These findings provide a descriptive and hypothesis-generating transcriptomic framework for understanding inflammatory macrophage activation and VSMC remodeling in human atherosclerosis.

atherosclerosis↗
PubMed2025

BTS: a scalable Bayesian Tissue Score for prioritizing GWAS variants and their functional contexts across >1000s of omics datasets.

MOTIVATION: statistics from genome-wide association studies (GWAS) are widely used in fine-mapping and colocalization analyses to identify causal variants and their enrichment in functional contexts, such as affected cell types and genomic features. With the expansion of functional genomic (FG) datasets, which now include hundreds of thousands of tracks across various cell and tissue types, it is critical to establish scalable algorithms integrating thousands of diverse FG annotations with GWAS results. RESULTS: We propose BTS (Bayesian Tissue Score), a novel, highly efficient algorithm uniquely designed for (i) identifying affected cell types and functional elements (context-mapping) and (ii) fine-mapping potentially causal variants in a context-specific manner using large collections of cell type-specific FG annotation tracks. BTS leverages GWAS summary statistics and annotation-specific Bayesian models to analyze genome-wide annotation tracks, including enhancers, open chromatin, and histone marks. We evaluated BTS on GWAS summary statistics for immune and cardiovascular traits, such as Inflammatory Bowel Disease (IBD), Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE), and Coronary Artery Disease (CAD). Our results demonstrate that BTS is over 100× more efficient in estimating functional annotation effects and context-specific variant fine-mapping compared to existing methods. Importantly, this large-scale Bayesian approach prioritizes both known and novel annotations, cell types, genomic regions, and variants and provides valuable biological insights into the functional contexts of these diseases. AVAILABILITY AND IMPLEMENTATION: Docker image is available at https://hub.docker.com/r/wanglab/bts with preinstalled BTS R package (https://bitbucket.org/wanglab-upenn/BTS-R) and BTS GWAS summary statistics analysis pipeline (https://bitbucket.org/wanglab-upenn/bts-pipeline).

Genome-Wide Association Study↗
PubMed2006

CD70 (TNFSF7) is expressed at high prevalence in renal cell carcinomas and is rapidly internalised on antibody binding.

In order to identify potential markers of renal cancer, the plasma membrane protein content of renal cell carcinoma (RCC)-derived cell lines was annotated using a proteomics process. One unusual protein identified at high levels in A498 and 786-O cells was CD70 (TNFSF7), a type II transmembrane receptor normally expressed on a subset of B, T and NK cells, where it plays a costimulatory role in immune cell activation. Immunohistochemical analysis of CD70 expression in multiple carcinoma types demonstrated strong CD70 staining in RCC tissues. Metastatic tissues from eight of 11 patients with clear cell RCC were positive for CD70 expression. Immunocytochemical analysis demonstrated that binding of an anti-CD70 antibody to CD70 endogenously expressed on the surface of A498 and 786-O cell lines resulted in the rapid internalisation of the antibody-receptor complex. Coincubation of the internalising anti-CD70 antibody with a saporin-conjugated secondary antibody before addition to A498 cells resulted in 50% cell killing. These data indicate that CD70 represents a potential target antigen for toxin-conjugated therapeutic antibody treatment of RCC.

Antibodies↗
PubMed2004

Genome-scale, biochemical annotation method based on the wheat germ cell-free protein synthesis system.

Since the complete genomic DNA sequencing of various species, attention has turned to the structural properties, and functional characteristics of proteins. Current cell-free protein expression systems from eukaryotes are capable of synthesizing proteins with high speed and accuracy; however, the yields are low due to their instability over time. This report reviews the high-throughput, genome-scale biochemical annotation method based on the cell-free system prepared from wheat embryos. We first briefly reviewed our highly efficient and robust wheat germ cell-free protein synthesis system, and then showed an application of the system for materialization and characterization of genetic information taking a cDNA library of protein kinase from Arabidopsis thaliana as an example. The procedure consists of: (1) fusion of the gene-of-interest to a purification-tag, amplified by the split-primer PCR method; (2) transcription and purification of mRNA; (3) cell-free protein synthesis in the bilayer system using 96-well titer plate; (4) affinity purification and activity measurement. We took 439 cDNAs encoding kinases among 1064 genes annotated so far, and they were translated in parallel into protein. Subsequent assay revealed 207 products having autophosphorylation activity. Furthermore, seven proteins out of 26 calcium-dependent protein kinase genes tested did phosphorylate a synthetic peptide substrate in the presence of calcium ion, demonstrating that the translation products, retained their substrate specificity. The information on biochemical function of gene products accumulated should revolutionize our understanding of biology and fundamentally alter the practice of medicine and influence other industries as well.

Arabidopsis↗
PubMed2026

Integrated multi-omics profiling identifies aging-related molecular signatures and convergent interferon signaling in systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is characterized by chronic immune activation and molecular alterations that overlap with aging-related biological processes. However, how these alterations are organized across molecular layers and whether they converge on shared regulatory networks remain incompletely understood. METHODS: We performed an integrative multi-omics analysis combining in-house proteomic and phosphoproteomic data from 130 patients with SLE and 90 healthy controls (HCs) and publicly available transcriptomic datasets comprising 1,461 SLE patients. Proteins and phosphorylation sites were annotated using established aging-related gene resources. Differential protein abundance and phosphorylation changes were analyzed across disease-status and disease-activity comparisons. Nominal P-value thresholds were used for exploratory feature selection, whereas FDR-adjusted P values were used to assess robustness after multiple-testing correction. Kinase-substrate enrichment, transcription factor annotation, and cell-type-resolved transcriptomic comparison were used to explore potential regulatory programs. RESULTS: We identified 128 nominally altered proteins annotated to aging-related biological processes, including genomic instability, mitochondrial dysfunction, and epigenetic alterations. Phosphoproteomic analysis revealed 36 nominally altered phosphorylation sites, including previously unreported sites in IFI16 (S153, S780) and PKCδ (S507, S664). Clustering analysis demonstrated heterogeneous protein co-regulation patterns across disease states. Kinase activity inference suggested altered activity of TBK1 and IKKβ. TF analysis further highlighted STAT1, RELA, and PML as potential central nodes within the inferred regulatory network. Notably, these multi-omic alterations were not randomly distributed but showed convergence toward shared signaling pathways, particularly those related to interferon responses. CONCLUSIONS: This integrative multi-omics study identifies inflammatory and interferon-dominated molecular alterations in SLE PBMCs that overlap with aging-related biological processes and converge on shared regulatory networks. These findings provide a hypothesis-generating framework for investigating the intersection between chronic immune activation and aging-related molecular remodeling in SLE.

Humans↗
PubMed2006

Establishment of the epithelial-specific transcriptome of normal and malignant human breast cells based on MPSS and array expression data.

INTRODUCTION: Diverse microarray and sequencing technologies have been widely used to characterise the molecular changes in malignant epithelial cells in breast cancers. Such gene expression studies to identify markers and targets in tumour cells are, however, compromised by the cellular heterogeneity of solid breast tumours and by the lack of appropriate counterparts representing normal breast epithelial cells. METHODS: Malignant neoplastic epithelial cells from primary breast cancers and luminal and myoepithelial cells isolated from normal human breast tissue were isolated by immunomagnetic separation methods. Pools of RNA from highly enriched preparations of these cell types were subjected to expression profiling using massively parallel signature sequencing (MPSS) and four different genome wide microarray platforms. Functional related transcripts of the differential tumour epithelial transcriptome were used for gene set enrichment analysis to identify enrichment of luminal and myoepithelial type genes. Clinical pathological validation of a small number of genes was performed on tissue microarrays. RESULTS: MPSS identified 6,553 differentially expressed genes between the pool of normal luminal cells and that of primary tumours substantially enriched for epithelial cells, of which 98% were represented and 60% were confirmed by microarray profiling. Significant expression level changes between these two samples detected only by microarray technology were shown by 4,149 transcripts, resulting in a combined differential tumour epithelial transcriptome of 8,051 genes. Microarray gene signatures identified a comprehensive list of 907 and 955 transcripts whose expression differed between luminal epithelial cells and myoepithelial cells, respectively. Functional annotation and gene set enrichment analysis highlighted a group of genes related to skeletal development that were associated with the myoepithelial/basal cells and upregulated in the tumour sample. One of the most highly overexpressed genes in this category, that encoding periostin, was analysed immunohistochemically on breast cancer tissue microarrays and its expression in neoplastic cells correlated with poor outcome in a cohort of poor prognosis estrogen receptor-positive tumours. CONCLUSION: Using highly enriched cell populations in combination with multiplatform gene expression profiling studies, a comprehensive analysis of molecular changes between the normal and malignant breast tissue was established. This study provides a basis for the identification of novel and potentially important targets for diagnosis, prognosis and therapy in breast cancer.

Biomarkers, Tumor↗
PubMed2003

Genetic variation and hematopoietic stem cell transplantation: expansion of the paradigm.

Genetic variation has been the mainstay of hematopoietic stem cell transplantation since the first transplants were attempted. A significant expansion of genetic knowledge is under way, as the draft sequence of the human genome is annotated. Hematopoietic stem cell transplantation is a field that will greatly benefit from this new knowledge, but the manner in which it is applied is daunting. Variation within key molecules related to hematopoietic stem cell transplant in combination with the current knowledge of human leukocyte antigen variation will serve to improve donor-recipient matches and clinical outcome.

Databases, Nucleic Acid↗
PubMed2002

Mutant laboratory mice with abnormalities in pigmentation: annotated tables.

Mammalian pigment cell research has recently entered a phase of significantly increased activity due largely to the exploitation of the many mutant mouse stocks that are coming on stream. Numerous transgenic, targeted mutagenesis (so-called 'knockouts'), conditional (so-called 'gene switch') and spontaneous mutant mice develop abnormal coat color phenotypes. The number of mice that exhibit such abnormalities is increasing exponentially as genetic engineering methods become routine. Since defined abnormalities in such mutant mice provide important clues to the as yet often poorly understood functional roles of many gene products, this overview includes a corresponding, annotated table of mutant mice with pigmentation alterations. These range from early developmental defects via a large array of coat color abnormalities to a melanoma metastasis model. This overview should provide helpful pointers to investigators who are looking for mouse models to explore or to compare functional activities of genes of interest and for comparing coat color phenotypes of spontaneous or genetically engineered mouse mutants with novel ones. Secondly, this review includes a table of mouse models of specific human diseases with genetically defined pigmentation abnormalities. In summary, this annotated table should serve as a useful reference for anyone interested in the molecular controls of pigmentation.

Animals↗
PubMed2001

In silico predictions of Escherichia coli metabolic capabilities are consistent with experimental data.

A significant goal in the post-genome era is to relate the annotated genome sequence to the physiological functions of a cell. Working from the annotated genome sequence, as well as biochemical and physiological information, it is possible to reconstruct complete metabolic networks. Furthermore, computational methods have been developed to interpret and predict the optimal performance of a metabolic network under a range of growth conditions. We have tested the hypothesis that Escherichia coli uses its metabolism to grow at a maximal rate using the E. coli MG1655 metabolic reconstruction. Based on this hypothesis, we formulated experiments that describe the quantitative relationship between a primary carbon source (acetate or succinate) uptake rate, oxygen uptake rate, and maximal cellular growth rate. We found that the experimental data were consistent with the stated hypothesis, namely that the E. coli metabolic network is optimized to maximize growth under the experimental conditions considered. This study thus demonstrates how the combination of in silico and experimental biology can be used to obtain a quantitative genotype-phenotype relationship for metabolism in bacterial cells.

Acetates↗
PubMed2004

Functional annotation of mouse mutations in embryonic stem cells by use of expression profiling.

Expression profiling offers a potential high-throughput phenotype screen for mutant mouse embryonic stem (ES) cells. We have assessed the ability of expression arrays to distinguish among heterozygous mutant ES cell lines and to accurately reflect the normal function of the mutated genes. Two ES cell lines hemizygous for overlapping regions of mouse Chromosome (Chr) 5 differed substantially from the wildtype parental line and from each other. Expression differences included frequent downregulation of hemizygous genes and downstream effects on genes mapping to other chromosomes. Some genes were affected similarly in each deletion line, consistent with the overlap of the deletions. To determine whether such downstream effects reveal pathways impacted by a mutation, we examined ES cell lines heterozygous for mutations in either of two well-characterized genes. A heterozygous mutation in the gene encoding the cell cycle regulator, cyclin D kinase 4 ( Cdk4), affected expression of many genes involved in cell growth and proliferation. A heterozygous mutation in the ATP binding cassette transporter family A, member 1 ( Abca1) gene, altered genes associated with lipid homeostasis, the cytoskeleton, and vesicle trafficking. Heterozygous Abca1 mutation had similar effects in liver, indicating that ES cell expression profile reflects changes in fundamental processes relevant to mutant gene function in multiple cell types.

ATP Binding Cassette Transporter 1↗
PubMed2002

Mnd1p: an evolutionarily conserved protein required for meiotic recombination.

We used a functional genomics approach to identify a gene required for meiotic recombination, YGL183c or MND1. MND1 was spliced in meiotic cells, extending the annotated YGL183c ORF N terminus by 45 aa. Saccharomyces cerevisiae mnd1-1 mutants, in which the majority of the MND1 coding sequence was removed, arrested before the first meiotic division with a phenotype reminiscent of dmc1 mutants. Physical and genetic analysis showed that these cells initiated recombination, but did not form heteroduplex DNA or double Holliday junctions, suggesting that Mnd1p is involved in strand invasion. Orthologs of MND1 were identified in protists, several yeasts, plants, and mammals, suggesting that its function has been conserved throughout evolution.

Amino Acid Sequence↗
PubMed2025

Bayesian Phylogenetic Lineage Reconstruction with Loss of Heterozygosity Mutations Derived from Single-Cell RNA Sequencing.

Mutations are acquired frequently, such t`hat each cell's genome inscribes its history of cell divisions. Loss of heterozygosity (LOH) accumulates throughout the genome, offering large encoding capacity for phylogenetic inference of cell lineage.In this chapter, we demonstrate a method, using single-cell RNA sequencing, for reconstructing cell lineages from inferred LOH events in a Bayesian manner, annotating the lineage with cell phenotypes, and marking developmental time points based on X-chromosome inactivation. This type of retrospective analysis could be incorporated into scRNA-seq pipelines and was initially developed to investigate Emx1+ cortical projection neuron and glia lineages from C57Bl/6J (B6) and CAST/EiJ (CA) interstrain F1 mice, describing progenitor cells giving rise to multiple cortical cell types through stereotyped expansion and distinct waves of neurogenesis.

Animals↗
PubMed2001

Simultaneous modelling of metabolic, genetic and product-interaction networks.

The creation of cell models from annotated genome information, as well as additional data from other databases, requires both a format and medium for its distribution. Standards are described for the representation of the data in the form of Document Type Definitions (DTDs) for XML files. Separate DTDs are detailed for genetic, metabolic and gene product-interaction networks, which can be used to hold information on individual subsystems, or which may be combined to create a whole cell DTD. In the execution of this work, a fifth DTD was also created for a metabolite thesaurus, which allows incorporation of metabolite synonyms and generic nomenclature data into the models. A gene-regulation classification scheme was also created, to facilitate incorporation of gene regulatory information in an efficient manner. The work is described with particular reference to the metabolic network of Escherichia coli, which contains 808 individual enzymes. The assignment of confidence levels to these data, through the use of Gene Ontology evidence codes, is highlighted. In silico investigations may now be performed using the mathematical simulation workbench, DBsolve, which incorporates the facility to introduce data directly from XML.

Computational Biology↗
PubMed2006

Genomic analysis of carbon source metabolism of Shewanella oneidensis MR-1: Predictions versus experiments.

Genomic sequences have been used to find the genetic foundation for carbon source metabolism in Shewanella oneidensis MR-1. Annotated S. oneidensis MR-1 gene products were examined for their sequence similarity to enzymes participating in pathways for utilization of carbon and energy as described in the BioCyc database (http://www.biocyc.org/) or in the primary literature. A picture emerges that relegates five- and six-carbon sugars to minor roles as carbon sources, whereas multiple pathways for utilization of up to three-carbon carbohydrates seem to be present. Capacity to utilize amino acids for carbon and energy is also present. A few contradictions emerged in which enzymes appear to be present by annotations but are not active in the cell according to physiological experiments. Annotations are based on close sequence similarity and will not reveal inactivity due to deleterious mutations or due to lack of coordination of regulation and transport. Genes for a few enzymes known by experiment to be active are not found in the genome. This may be due to extensive divergence after duplication or convergence of function in separate lines in evolution rendering activities undetectable by sequence similarity. To minimize false predictions from protein sequences, we have been conservative in predicting pathways. We did not predict any pathway when, although a partial pathway was seen it was composed largely of enzymes already accounted for in any other complete pathway. This is an example of how a biochemically oriented sequence analysis can generate questions and direct further experimental investigation.

Bacterial Proteins↗